Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer’s Disease: An Integrated Epigenomic-Transcriptomic Analysis

Abstract

Alzheimer’s disease (AD) is characterized by the abnormal deposition of amyloid-β (Aβ) plaques and tau tangles in the brain and accompanied with cognitive impairment. However, the fundamental cause of this disease remains elusive. To elucidate the molecular processes related to AD, we carried out an integrated analysis utilizing gene expression microarrays (GSE36980 and GSE5281) and DNA methylation microarray (GSE66351) in temporal cortex of AD patients from the Gene Expression Omnibus (GEO) database. We totally discovered 409 aberrantly methylated and differentially expressed genes. These dysregulated genes were significantly enriched in biological processes including cell part morphogenesis, chemical synaptic transmission and regulation of Aβ formation. Through convergent functional genomic (CFG) analysis, expression cross-validation and clinicopathological correlation analysis, higher TGFBR3 level was observed in AD and positively correlated with Aβ accumulation. Meanwhile, the promoter methylation level of TGFBR3 was reduced in AD and negatively associated with Aβ level and advanced Braak stage. Mechanically, TGFBR3 might promote Aβ production by enhancing β- and γ-secretase activities. Further investigation revealed that TGFBR3 may exert its functions via Synaptic vesicle cycle, Calcium signaling pathway and MAPK signal pathway by regulating hub genes GNB1, GNG3, CDC5L, DYNC1H1 and FBXW7. Overall, our findings highlighted TGFBR3 as an AD risk gene and might be used as a diagnostic biomarker and therapeutic target for AD treatment.

Identification and validation of immune‐related methylated genes as diagnostic and prognostic biomarkers of nasopharyngeal carcinoma

“…TGFBR3 expression was observed to be elevated in Alzheimer's disease (AD), while its promoter methylation level of cg17074213 decreased considerably. 58 In our study, we found that TGFBR3 mRNA increased in NPC cells following treatment with 5-Aza-CdR. The above results suggested that aberrant expression of TGFBR3 in NPC was associated with DNA methylation.…”

The Distant Molecular Effects on the Brain by Cancer Treatment

“…Adar encodes for a protein called ADAR1, and increased expression of ADAR1 has been associated with stress-induced cognitive impairment in mice [37]. Gnb1 expression engages in G-protein-coupled receptors by acting as a molecular switch in the signal transduction [38]. The increased expression of brain Gnb1, which we also observed in the DOX-only-treated mice, has been linked to anxiety and depressive behavior [39].…”

“…Doxorubicin has been shown to cause anxiety in humans and anxiety-like behavior in mice and rats [40][41][42][43]. In humans, Gnb1 expression has been shown to be increased in neurological diseases including Alzheimer's disease [38]. Lastly, Vim encodes for vimentin, which is a marker of reactive astrocytes in reactive gliosis, and its expression is increased in neurodegenerative diseases [44,45].…”

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“…Hypomethylation increases with age and leads to an unstable genome, with activation of some tumor promoter genes 134,135 . Hypomethylation of CpG islands (cytosine-guanine pairs) promotes AD 136 , LBD 137,138 , and PD 139 .…”